Patent EA-000840-B1 (EA)
Title: Method for the selective treatment of cell growth and cell differention and use pharmaceutical composition thereof comprising aryl and heteroarylquinoazoline compounds therefor
Inventor: MYERS MICHAEL R
IPC: C07D215/233
Filed: 1996-06-06
Abstract: 1. A method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type 2 (HER2) comprising administering to a patient in need of such treatment an HER2 receptor inhibiting effective amount of a compound of the formula:   wherein A is a substituted or unsubstituted mono- or bi-cyclic aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring system of about 5 to about 12 atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO2, OCH2, CR4=CR4, C [triple bond] C, NR4 or NR4CH2; R independently includes hydrogen, alkyl, phenyl, halophenyl, aralkyl, hydroxy, alkoxy, aryloxy, acyloxy, halo, haloalkyl, amino, mono- and dialkylamino, acylamino, carboxy, amido, mono- and di-alkylamido, alkylthio, alkylsulfinyl, and alkylsulfonyl; R4 is hydrogen, alkyl or aralkyl; and  R5, R6, R7 and R8 are independently hydrogen, alkoxy or aralkoxy; or a pharmaceutically acceptable salt thereof. 2. A method according to claim 1 where: A is a substituted or unsubstituted monocyclic aryl or heteroaryl ring selected from phenyl, pyrrolyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl and oxazolyl. 3. A method according to claim 1 where: A is a substituted or unsubstituted bicyclic aryl or heteroaryl ring selected from naphthyl, tetralinyl, 1 ,2,3,4-tetrahydroquinolinyl, benzofuryl, benzothienyl, indanyl, indolyl, indolinyl, 1,3-benzodioxolyl, benzodioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. 4. A method according to claim 1 where: A is a substituted or unsubstituted monocyclic cycloalkyl or heterocycloalkyl ring selected from cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, piperdinyl, piperazinyl, morpholinyl or decahydroquinolinyl. 5. A method according to claim 1 where: A is a substituted or unsubstituted bicyclic cycloalkyl or heterocycloalkyl ring selected from decalinyl or decahydroquinolinyl. 6. A method according to claim 1 where: A is substituted and unsubstituted phenyl, pyridyl, thienyl, furyl, pyrazolyl, naphthyl, tetralinyl, 1,2,3,4-tetrahydroquinolinyl, indanyl, indolyl, indolinyl, quinolinyl, tetrahydroqu inolinyl, cyclohexyl, piperdinyl or piperazinyl; X is a bond, O, S, or NR4; R is hydrogen, alkyl, alkoxy, halo, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenyl and aralkyl; R4 is hydrogen, alkyl or aralkyl; and R5, R6, R7, and R8 are independently hydrogen or alkoxy. 7. A method according to claim 6 where: A is substituted and unsubstituted phenyl, naphthyl or indolyl; X is a bond; R is hydrogen, methoxy, ethoxy,chloro, trifluoromethyl, methylsulfonyl, phenyl and benzyl; R4 is hydrogen, methyl or benzyl; and R5, R6, R7, and R8 are independently hydrogen or methoxy. 8. A method according to claim 2 where the compound administered is 4-(2phenylethylenyl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable thereof. 9. A method according to claim 3 where said compound administered is 6,7-dimethoxy-4-naphthalen-1-yl-ethynylquinazoline or a pharmaceutically acceptable thereof. 10. A method according to claim 6 where said compound administered is selected from: 4-(2-methoxypyridin-5-yl)-6,7-dimethoxyquinazoline; 4-(4-phenylpiperidin-1-yl)-6,7-dimethoxyquinazoline; 4-[4-(3-chlorophenyl)piperazin-1-yl]-6,7-dimethoxyquinazoline; and 4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable thereof. 11. A method according to claim 6 where said compound administered is selected from: 6,7-dimethoxy-4-(β-naphthylamino)quinazoline; 4-[N-(5-indanyl)amino]-6,7-dimethoxyquinazoline; N-benzyl-N-(6,7-dimethoxyquinazolin-4-yl)-N-phenylamine; 6,7-dimethoxy-4-(N-methylanilino)quinazoline; N-(3-chlorophenyl)-N-(6,7-dimethoxyquinazolin-4-yl)-N-methylamine; 4-(3-aminopyrazolyl)-6,7-dimethoxyquinazoline; and 4-(cyclohexylanilino)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable thereof. 12. A method according to claim 6 where the compound administered is 6,7dimethoxy-4-(α-naphthylamino)quinazoline or a pharmaceutically acceptable salt thereof. 13. A method according to claim 6 where said compound administered is 6,7dimethoxy-4-(α-naphthylamino)quinazoline or a pharmaceutically acceptable salt thereof. 14. A method according to claim 6 where said compound administered is selected from: 4-(naphthalen-1-yl)-6,7-dimethoxyquinazoline; 4-(naphthalen-2-yl)-6,7-dimethoxyquinazoline; 4-(3-phenylphenyl)-6,7-dimethoxyquinazoline; 4-(indol-3-yl)-6,7-dimethoxyquinazoline; and 4-(1 -methylindol-3-yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof. 15. A method according to claim 7 where the compound administered is 4-(1-benzylindol-3-yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof. 16. Use of pharmaceutical composition comprising an HER2 receptor inhibiting effective amount of a compound of the formula:   wherein A is a substituted or unsubstituted mono- or bi-cyclic aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring system of about 5 to about 12 atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO2, OCH2, CR4=CR4, C [triple bond] C, NR4 or NR4CH2; R independently includes hydrogen, alkyl, phenyl, halophenyl, aralkyl, hydroxy, alkoxy, aryloxy, acyloxy, halo, haloalkyl, amino, mono- and dialkylamino, acylamino, carboxy, amido, mono- and di-alkylamido, alkylthio, alkylsulfinyl, and alkylsulfonyl; R4 is hydrogen, alkyl or aralkyl; and R5, R6, R7 and R8 are independently hydrogen, alkoxy or aralkoxy; or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier for selective treatment of cell growth and cell differentiation. 17. Use of composition according to claim 16 where: A is substituted and unsubstituted phenyl, pyridyl, thienyl, furyl, pyrazolyl, naphthyl, tetralinyl, 1,2,3,4-tetrahydroquinolinyl, indanyl, indolyl, indolinyl, quinolinyl, tetrahydroquinolinyl, cyclohexyl, piperdinyl or piperazinyl; X is a bond, O, S, or NR4; R is hydrogen, alkyl, alkoxy, halo, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenyl and aralkyl; R4 is hydrogen, alkyl or aralkyl; and R5, R6, R7, and R8 are independently hydrogen or alkoxy. 18. A composition according to claim 17 where the compound is 6,7-dimethoxy-4-(α-naphthylamino)quinazoline or a pharmaceutically acceptable salt thereof. 19. A composition according to claim 17 where the compound is 4-(1-benzylindol-3-yl)-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.